Structure-activity relationships and modes of action of 9-anilinoacridines against chloroquine-resistant Plasmodium falciparum in vitro.

An in vitro investigation of the structure-activity profiles for a range of 9-anilinoacridines on drug-resistant Plasmodium falciparum is reported. C-3, 6-diamino substitution, low lipophilicity, and high pKa values substantially increased the activities of the 9-anilinoacridines tested. There appeared to be no correlation between DNA binding and antimalarial activity. 3,6-Diamino-1'-amino-9-anilinoacridine (compound 13) was the most active compound tested; it had a 50% inhibitory concentration of 25 nM. In vitro mammalian cell growth assays showed compound 13 to be one of the least cytotoxic 9-anilinoacridines (50% inhibitory concentration, 15 microM). Both compound 13 and the antimalarial drug pyronaridine inhibited the decatenation activity of P. falciparum DNA topoisomerase II at concentrations of 10 and 11 microM, respectively.